EP1578439B1 - Low dose methods for treating disorders in which tnf-alpha activity is detrimental - Google Patents

Low dose methods for treating disorders in which tnf-alpha activity is detrimental Download PDF

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Publication number
EP1578439B1
EP1578439B1 EP03809644A EP03809644A EP1578439B1 EP 1578439 B1 EP1578439 B1 EP 1578439B1 EP 03809644 A EP03809644 A EP 03809644A EP 03809644 A EP03809644 A EP 03809644A EP 1578439 B1 EP1578439 B1 EP 1578439B1
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Prior art keywords
tnfα
antibody
arthritis
human
tnf
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EP03809644A
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German (de)
English (en)
French (fr)
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EP1578439A4 (en
EP1578439A2 (en
Inventor
Zehra Kaymakcalan
Robert Kamen
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AbbVie Biotechnology Ltd
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Abbott Biotech Ltd Bermuda
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Priority to EP10182448A priority Critical patent/EP2332565A1/en
Priority to EP10181959A priority patent/EP2295071A1/en
Priority to SI200332033T priority patent/SI1578439T1/sl
Publication of EP1578439A2 publication Critical patent/EP1578439A2/en
Publication of EP1578439A4 publication Critical patent/EP1578439A4/en
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Publication of EP1578439B1 publication Critical patent/EP1578439B1/en
Priority to CY20111100933T priority patent/CY1113524T1/el
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Definitions

  • Tumor necrosis factor a is a cytokine produced by numerous cell types, including monocytes and macrophages, that was originally identified based on its capacity to induce the necrosis of certain mouse tumors (see e.g ., Old, L. (1985) Science 230:630-632 ). Subsequently, a factor termed cachectin, associated with cachexia, was shown to be the same molecule as TNF ⁇ . TNF ⁇ has been implicated in mediating shock (see e.g ., Beutler, B. and Cerami, A. (1988) Annu. Rev. Biochem. 57:505-518 ; Beutler, B. and Cerami, A. (1989) Annu. Rev. Immunol.
  • TNF ⁇ has been implicated in the pathophysiology of a variety of other human diseases and disorders, including sepsis, infections, autoimmune diseases, transplant rejection and graft-versus-host disease (see e.g ., Moeller, A., et al. (1990) Cytokine 2:162-169 ; U.S. Patent No. 5,231,024 to Moeller et al .; European Patent Publication No. 260 610 B1 by Moeller, A., et al . Vasilli, P. (1992) Annu. Rev. Immunol. 10:411-452 ; Tracey, K.J. and Cerami, A. (1994) Annu. Rev. Med. 45:491-503 ).
  • hTNF ⁇ human TNF ⁇
  • therapeutic strategies have been designed to inhibit or counteract hTNF ⁇ activity.
  • antibodies that bind to, and neutralize, hTNF ⁇ have been sought as a means to inhibit hTNF ⁇ activity.
  • Some of the earliest of such antibodies were mouse monoclonal antibodies (mAbs), secreted by hybridomas prepared from lymphocytes of mice immunized with hTNF ⁇ (see e.g ., Hahn T; et al., (1985) Proc Natl Acad Sci USA 82: 3814-3818 ; Liang, C-M., et al. (1986) Biochem. Biophys. Res. Commun.
  • mouse anti-hTNF ⁇ antibodies often displayed high affinity for hTNF ⁇ (e.g., Kid ⁇ 10 -9 M) and were able to neutralize hTNF ⁇ activity
  • their use in vivo may be limited by problems associated with administration of mouse antibodies to humans, such as short serum half life, an inability to trigger certain human effector functions and elicitation of an unwanted immune response against the mouse antibody in a human (the "human anti-mouse antibody” (HAMA) reaction).
  • HAMA human anti-mouse antibody
  • murine anti-hTNF ⁇ antibodies have been genetically engineered to be more "human-like.”
  • chimeric antibodies in which the variable regions of the antibody chains are murine-derived and the constant regions of the antibody chains are human-derived, have been prepared ( Knight, D.M, et al. (1993) Mol. Immunol. 30:1443-1453 ; PCT Publication No. WO 92/16553 by Daddona, P.E., et al . ).
  • humanized antibodies in which the hypervariable domains of the antibody variable regions are murine-derived but the remainder of the variable regions and the antibody constant regions are human-derived, have also been prepared ( PCT Publication No.
  • HACA human anti-chimeric antibody
  • a preferred hTNF ⁇ inhibitory agent to murine mAbs or derivatives thereof would be an entirely human anti-hTNF ⁇ antibody, since such an agent should not elicit the HAMA reaction, even if used for prolonged periods.
  • Human monoclonal autoantibodies against hTNF ⁇ have been prepared using human hybridoma techniques ( Boyle, P., et al. (1993) Cell. Immunol. 152:556-568 ; Boyle, P., et al. (1993) Cell. Immunol. 152:569-581 ; European Patent Application Publication No.
  • human antibodies such as recombinant human antibodies, that bind soluble hTNF ⁇ with high affinity and slow dissociation kinetics and that have the capacity to treat disorders in which TNF ⁇ activity is detrimental, are still needed.
  • the invention pertains to a human anti-TNFa antibody which is either D2E7, or a human anti-TNFa antibody with equivalent properties to D2E7 which dissociates from human TNFa with a K d of 1 x 10 -8 M or less and a k off rate constant of 1x10 -3 s -1 or less, both determined by surface plasmon resonance, and neutralizes human TNFa cytotoxicity in a standard in vitro L929 assay with an IC 50 of 1 x 10 -7 M or less, for use in the treatment or alleviation of arthritis, wherein the anti-TNFa antibody is to be administered in a low dose of 0.01-0.11 mg/kg, such that the arthritis is treated or alleviated.
  • the invention pertains to a human anti-TNF ⁇ antibody which is either D2E7, or a human anti-TNF ⁇ antibody with equivalent properties to D2E7 which dissociates from human TNF ⁇ with a K d of 1 x 10 -8 M or less and a k off rate constant of 1 x 10 -3 s -1 or less, both determined by surface plasmon resonance, and neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC 50 of 1 x 10 -7. M or less, for use in the treatment or alleviation of arthritis, wherein the anti-TNF ⁇ antibody is to be administered in a low dose of 0.01-0.11 mg/kg, such that the arthritis is treated or alleviated.
  • human TNF ⁇ (abbreviated herein as huTNF, hTNF ⁇ , or simply hTNF), as used herein, is intended to refer to a human cytokine that exists as a 17 kD secreted form and a 26 kD membrane associated form, the biologically active form of which is composed of a trimer of noncovalently bound 17 kD molecules.
  • the structure of hTNF ⁇ is described further in, for example, Pennica, D., et al. (1984) Nature 312:724-729 ; Davis, J.M., et al. (1987) Biochemistry 26:1322-1326 ; and Jones, E.Y., et al. (1989) Nature 338:225-228 .
  • the term human TNF ⁇ is intended to include recombinant human TNF ⁇ (rhTNF ⁇ ), which can be prepared by standard recombinant expression methods or purchased commercially (R & D Systems, Catalog No. 210-TA, Minneapolis, MN
  • TNF ⁇ inhibitor includes agents which inhibit TNF ⁇ .
  • TNF ⁇ inhibitors include etanercept (ENBREL, Immunex), infliximab (REMICADE, Johnson and Johnson), human anti-TNF monoclonal antibody (D2E7, Knoll Pharmaceuticals), CDP 571 (Cell tech), and CDP 870 (Celltech) and other compounds which inhibit TNF ⁇ activity, such that when administered to a subject suffering from or at risk of suffering from a disorder in which TNF ⁇ activity is detrimental, the disorder is treated.
  • the term also includes each of the anti-TNF ⁇ human antibodies and antibody portions described herein as well as those described in U.S. Patent Nos. 6,090,382 and 6,258,562 B1 , in U.S. Patent No. 6,509,015 and in US 2003/0092059 A1 .
  • antibody is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CH1, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • Antibodies are described in further detail in U.S. Patent Nos. 6,090,382 and 6,258,562 B1 , in U.S. Patent No. 6,509,015 and in US 2003/0092059 A1 .
  • antigen-binding portion of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g ., hTNF ⁇ ). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment ( Ward et al., (1989) Nature 341:544-546 ), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR).
  • a Fab fragment a monovalent fragment consisting of the VL, VH, CL and CH1 domains
  • a F(ab') 2 fragment a bivalent fragment comprising two Fab fragments linked by
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426 ; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883 ).
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody.
  • Other forms of single chain antibodies, such as diabodies are also encompassed.
  • Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g ., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448 ; Poljak, R.J., et al. (1994) Structure 2:1121-1123 ).
  • Antibody portions are described in further detail in U.S. Patent Nos. 6,090,382 and 6,258,562 B1 , in U.S. Patent No. 6,509,015 and in US 2003/0092059 A1 .
  • the present invention pertains to a human anti-TNF ⁇ antibody which is either D2E7, or a human anti-TNF ⁇ antibody with equivalent properties to D2E7 which dissociates from human TNF ⁇ with a K d of 1 x 10 -8 M or less and a k off rate constant of 1 x 10 -3 s -1 or less, both determined by surface plasmon resonance, and neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC 50 of 1 x 10 -7 M or less, for use in the treatment or alleviation of arthritis, wherein the anti-TNF ⁇ antibody is to be administered in a low dose of 0.01-0.11 mg/kg, such that the arthritis is treated or alleviated.
  • such isolated human antibody dissociates from human TNF* with a K off of 5 x 10 -4 s -1 or less, or even more preferably, with a K off 1 x 10 -4 s -1 or less. More preferably, the isolated human antibody neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC 50 of 1 x 10 -8 M or less, even more preferably with an IC 50 of 1 x 10 -9 M or less and still more preferably with an IC 50 of 5 x 10 -10 M or less.
  • low dose refers to an amount of TNF ⁇ inhibitor which is administered to a subject, wherein the amount is substantially lower than that ordinarily employed.
  • a “low dose therapy” includes a treatment regiment which is based on administering a low dose of a TNF ⁇ inhibitor.
  • a low dose of D2E7 is considered 0.01-0.11 mg/kg.
  • Such low dose may be used to treat rheumatoid arthritis and symptoms associated with the disease.
  • symptoms which can be treated using low dose therapy of D2E7 include bone erosion, cartilage erosion, inflammation, and vascularity.
  • Low doses of a TNF ⁇ inhibitor are advantageous for a number of reasons, including the reduction in the frequency and severity of side effects which may be associated with the normal prescribed dose of TNF ⁇ inhibitor.
  • TNF ⁇ has been implicated in the pathophysiology of a wide variety of disorders (see e.g., Moeller, A., et al. (1990) Cytokine 2:162-169 ; U. S. Patent No. 5,231,024 to Moeller et al .; European Patent Publication No. 260 610 B1 by Moeller, A ).
  • methods for inhibiting TNF ⁇ activity in a subject suffering from such a disorder which method comprises administering to the subject low dose of the antibody such that TNF ⁇ activity in the subject is inhibited.
  • the TNF ⁇ is human TNF ⁇ and the subject is a human subject.
  • the subject can be a mammal expressing a TNF ⁇ with which an antibody of the invention cross-reacts.
  • the antibody is to be administered to a human subject for therapeutic purposes in low doses of 0.01-0.11 mg/kg.
  • a low dose of the antibody can be administered to a non-human mammal expressing a TNF ⁇ with which the antibody cross-reacts (e.g ., a primate, pig or mouse) for veterinary purposes or as an animal model of human disease.
  • a primate, pig or mouse for veterinary purposes or as an animal model of human disease.
  • animal models may be useful for evaluating the therapeutic efficacy of antibodies (e.g ., testing of dosages and time courses of administration).
  • a disorder in which TNF ⁇ activity is detrimental is intended to include diseases and other disorders in which the presence of TNF ⁇ in a subject suffering from the disorder has been shown to be or is suspected of being either responsible for the pathophysiology of the disorder or a factor that contributes to a worsening of the disorder.
  • treating a disorder in which TNF ⁇ activity is detrimental relates to treating arthritis and includes, but is not limited to, alleviating symptoms associated with said disorder.
  • a disorder in which TNF ⁇ activity is detrimental is a disorder in which inhibition of TNF ⁇ activity is expected to alleviate the symptoms and/or progression of the disorder.
  • Such disorders may be evidenced, for example, by an increase in the concentration of TNF ⁇ in a biological fluid of a subject suffering from the disorder (e. g., an increase in the concentration of TNF ⁇ in serum, plasma, synovial fluid, etc . of the subject), which can be detected, for example, using an anti-TNF ⁇ antibody as described above.
  • an increase in the concentration of TNF ⁇ in a biological fluid of a subject suffering from the disorder e. g., an increase in the concentration of TNF ⁇ in serum, plasma, synovial fluid, etc . of the subject
  • an anti-TNF ⁇ antibody as described above.
  • the use of a low dose of the antibodies in the treatment of arthritis, in particular rheumatoid arthritis are discussed further below.
  • a low dose of the antibody is administered to the subject in combination with another therapeutic agent, as described below.
  • TNF ⁇ has been implicated in activating tissue inflammation and causing joint destruction in rheumatoid arthritis (see e.g ., Moeller, A., et al. (1990) Cytokine 2:162-169 ; U. S. Patent No. 5,231,024 to Moeller et al .; European Patent Publication No. 260 610 B 1 by Moeller, A .; Tracey and Cerami, supra; Arend, W. P. and Dayer, J-M. (1995) Arth. Rheum. 38:151-160 ; Fava, R. A., et al. (1993) Clin. Exp. Immunol. 94:261-266 ).
  • Chimeric and humanized murine anti-hTNF ⁇ antibodies have undergone clinical testing for treatment of rheumatoid arthritis (see e . g ., Elliott, M. J., et al. (1994) Lancet 344:1125-1127 ; Elliot, M. J., et al. (1994) Lancet 344:1105-1110 ; Rankin, E. C., et al. (1995) Br.J. Rheumatol. 34:334-342 ).
  • Low doses of anti-TNF ⁇ antibodies in accordance with the invention as defined above can be used to treat rheumatoid arthritis.
  • Low doses of anti-TNF ⁇ antibodies can be used to treat rheumatoid arthritis by alleviating symptoms associated with said disorder.
  • symptoms or signs commonly associated with rheumatoid arthritis include, but are not limited to, bone erosion in the joints, cartilage erosion in the joints, inflammation in the joints, vascularity in the joints, and combinations thereof.
  • Other examples of symptoms associated with rheumatoid arthritis include weight gain, joint distortion, swelling of the joints, joint deformation, ankylosis on felxion, severely impaired movement, and combinations thereof.
  • the human antibodies in accordance with the invention can be used to treat rheumatoid arthritis, osteoarthritis and gouty arthritis.
  • the antibody is administered systemically, although for certain disorders, local administration of the antibody at a site of inflammation may be beneficial (e. g., local administration in the joints in rheumatoid arthritis, alone or in combination with a cyclohexane-ylidene derivative as described in PCT Publication No. WO 93/19751 ).
  • the antibody also can be administered with one or more additional therapeutic agents useful in the treatment of autoimmune diseases, as discussed further in subsection II.
  • the antibodies can also be used to treat juvenile rheumatoid arthritis, psoriatic arthritis, and ostoarthritis.
  • the antibodies disclosed herein can be incorporated into pharmaceutical compositions suitable for low dose administration to a subject.
  • the pharmaceutical composition comprises an antibody and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody, antibody portion, or other TNF ⁇ inhibitor.
  • compositions may be in a variety of forms suitable for low dose administration. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g ., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions e.g ., injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the preferred form depends on the intended mode of administration and therapeutic application. Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies or other TNF ⁇ inhibitors.
  • the preferred mode of administration is parenteral (e.g ., intravenous, subcutaneous, intraperitoneal, intramuscular).
  • a low dose of the antibody is administered by intravenous infusion or injection.
  • a low dose of the antibody is administered by intramus
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration.
  • Sterile injectable solutions can be prepared by incorporating a low dose of the active compound (i.e ., antibody, antibody portion, or other TNF ⁇ inhibitor) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • packaged pharmaceutical compositions which comprise a low dose of the antibody and instructioris for using the inhibitor to treat a particular disorder in which TNF ⁇ activity is detrimental, as described above.
  • the pharmaceutical compositions may include a "therapeutically effective amount” or a “prophylactically effective amount” of an antibody.
  • a “therapeutically effective amount” is an amount which is determined to be required to eliminate said disorder or to reduce and/or alleviate the symptoms of said disorder, as long as a “therapeutically effective amount” refers to an amount which is effective, at low doses of 0.01-0.11 mg/kg and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of the antibody may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody are outweighed by the therapeutically beneficial effects.
  • Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single bolus may be administered, several divided low doses may be administered over time or the low dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in low dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the range in accordance with the invention for a therapeutically or prophylactically effective amount of the antibody is 0.01-0.11 mg/kg. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • the low dose of the antibody administered to a subject is between about 0.01-0.11 mg/kg, such as 0.06-0.11 mg/kg.
  • the antibody is D2E7.
  • Ranges intermediate to the above recited dosages are also intended to be part of this invention. For example, ranges of values using a combination of any of the above recited values as upper and/or lower limits are intended to be included.
  • the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978 .
  • a low dose of an antibody may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the compound (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
  • the compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • a low dose of the antibody is coformulated with and/or coadministered with one or more additional therapeutic agents that are useful for treating arthritis.
  • a low dose of the anti-hTNF ⁇ antibody may be coformulated and/or coadministered with one or more additional antibodies that bind other targets (e.g ., antibodies that bind other cytokines or that bind cell surface molecules), one or more cytokines, soluble TNF ⁇ receptor (see e.g ., PCT Publication No.
  • WO 94/06476 and/or one or more chemical agents that inhibit hTNF ⁇ production or activity (such as cyclohexane-ylidene derivatives as described in PCT Publication No. WO 93/19751 ).
  • a low dose of one or more antibodies may be used in combination with two or more of the foregoing therapeutic agents.
  • Such combination therapies may advantageously utilize even lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the various monotherapies.
  • combination with a therapeutic agent includes coadministration of a low dose of the antibody with a therapeutic agent, administration of a low dose of the antibody first, followed by the therapeutic agent and administration of the therapeutic agent first, followed by the low dose of the antibody.
  • Specific therapeutic agent (s) are generally selected based on the particular disorder being treated, as discussed below.
  • Nonlimiting examples of therapeutic agents for rheumatoid arthritis with which a low dose of the antibody can be combined include the following: non-steroidal anti-inflammatory drug (s) (NSAIDs); cytokine suppressive anti-inflammatory drug(s) (CSAIDs); CDP- 571/BAY-10-3356 (humanized anti-TNF ⁇ antibody; CelltechBayer); cA2 (chimeric anti-TNF ⁇ antibody; Centocor); 75 kdTNFR-IgG (75 kD TNF receptor-IgG fusion protein; Immunex; see e.g., Arthritis & Rheumatism (1994) Vol. 37, S295 ; J. Invest. Med. (1996) Vol.
  • NSAIDs non-steroidal anti-inflammatory drug
  • CSAIDs cytokine suppressive anti-inflammatory drug(s)
  • CDP- 571/BAY-10-3356 humanized anti-TNF ⁇ antibody; CelltechBayer
  • cA2 chimeric anti-TN
  • Anti-Tac humanized anti-IL-2R ⁇ ; Protein Design Labs/Roche
  • IL-4 anti-inflammatory cytokine; DNAX/Schering
  • IL-10 SCH 52000; recombinant IL-10, anti-inflammatory cytokine; DNAX/Schering
  • IL-4 IL-10 and/or IL-4 agonists ( e.g ., agonist antibodies)
  • IL-1RA IL-1 receptor antagonist; Synergen/Amgen
  • TNF-bp/s-TNFR soluble TNF binding protein; see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S284 ; Amer. J. Physiol.
  • R973401 phosphodiesterase Type IV inhibitor; see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S282 ); MK-966 (COX-2 Inhibitor; see e.g ., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S81 ); Iloprost (see e.g., Arthritis & Rheumatism (1996) Vol. 39, No.
  • T-614 cytokine inhibitor; see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S282 ); prostaglandin E1 (see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S282 ); Tenidap (non-steroidal anti-inflammatory drug; see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S280 ); Naproxen (non-steroidal anti-inflammatory drug; see e.g., Neuro Report (1996) Vol. 7, pp.
  • ICE inhibitor inhibitor of the enzyme interleukin-1 ⁇ converting enzyme
  • zap-70 and/or lck inhibitor inhibitor of the tyrosine kinase zap-70 or lck
  • VEGF inhibitor and/or VEGF-R inhibitor inhibitortos of vascular endothelial cell growth factor or vascular endothelial cell growth factor receptor; inhibitors of angiogenesis
  • corticosteroid anti-inflammatory drugs e.g ., SB203580
  • TNF-convertase inhibitors anti-IL-12 antibodies
  • interleukin-11 see e.g., Arthritis & Rheumatism (1996) Vol. 39, No.
  • interleukin-13 see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S308 ); interleukin-17 inhibitors (see e.g., Arthritis & Rheumatism (1996) Vol. 39, No.
  • Tg197 transgenic murine model of rheumatoid arthritis
  • RA rheumatoid arthritis
  • Infliximab is a human-mouse chimeric antibody
  • etanercept is a p75 TNF receptor construct.
  • D2E7 is a fully human antibody derived from a human immunoglobulin gene library.
  • Transgenic mice, Tg197 carry the human TNF ⁇ gene and spontaneously develop a disease similar to human rheumatoid arthritis ( Keffer, J. et al, 1991, EMBO J. 10:4025 ).
  • arthritic disease including rheumatoid arthritis, include slower weight gain, joint distortion and swelling, joint deformation and ankylosis and impaired movement. Histopathological findings include hyperplasia of the synovial membrane, leukocyte infiltration, pannus formation, articular cartilage and bone destruction. Administration of anti-TNF agents prevents the development of polyarthritis in a dose dependent manner.
  • Infliximab (Remicade) and Etanercept (Enbrel) are two anti-TNF drugs approved for rheumatoid arthritis.
  • Remicade is a human-mouse chimeric IgG 1 antibody and Enbrel is a fusion protein made up of extra-cellular domain of the p75 TNF receptor and the constant region of IgG 1 molecule.
  • D2E7 is a fully human antibody of the IgG 1 ,kappa class selected from human immunoglobulin gene libraries. All three anti-TNF agents bind to human TNF with relatively similar potency.
  • the intrinsic affinities of D2E7, Remicade and Enbrel for TNF are 8.6x10- 11 , 9.5x10 -11 and 15.7x10 -11 M (Kd values), respectively.
  • the kinetics of binding to TNF are similar for the antibodies D2E7 and Remicade.
  • Enbrel on the other hand, binds to and dissociates from TNF fast.
  • the 16 minute half-life of Enbrel:TNF complex is considerably shorter than the 184 and 255 minute half-lives for Remicade and D2E7:TNF complexes, respectively.
  • a BIAcore 3000 instrument was used to derive kinetic parameters of binding between human TNF and anti-TNF agents.
  • Biosensor chips were covalently coupled with a goat anti-human Fc antibody.
  • Anti-TNF agents D2E7, Remicade and Enbrel
  • Binding data were analyzed to derive the kinetic parameters, which are described in Table 1.
  • Tg197 mice were used as a model for studying the effects of a low dose regiment of D2E7, Remicade, and Enbrel on relieving symptoms commonly associated with rheumatoid arthritis.
  • Human TNF transgenic mice were identified and verified by PCR. From the first week of age, separate litters of Tg197 mice were assigned to different study groups. Tg197 mice heterozygous for the human TNF gene received weekly intraperitoneal doses of D2E7, Remicade or Enbrel. Each drug treatment dose group consisted of mice from a single litter. The control group received the phosphate buffered saline diluent and consisted of mice from 4 litters. Weights of animals in each group were recorded weekly prior to dosing. Each group received one i.p. injection per week as follows:
  • D2E7 offered more protection than Remicade at the same doses. Furthermore, the onset of disease was delayed in mice treated with 0.5 mg/kg of D2E7 up to 5 weeks, and with mice treated with 0.1 mg/kg doses of D2E7 up to 4 weeks ( Figure 1 ). In contrast, the onset of disease was delayed in mice treated with either 0.1 mg/kg or 0.5 mg/kg of Remicade for only 3 weeks ( Figure 2 ).
  • TNF levels were measured for each mouse in treatment groups. Results from the study are shown in Figure 6 . For each treatment group, mean ⁇ standard error of TNF levels are indicated in the graph. A solid line at each graph is drawn at 2 ng/mL TNF level for orientation purpose. In the untreated group, serum huTNF levels were low, 0.1 and 0.2 ng/mL at 5 and 10 weeks, respectively. Weekly administration of anti-TNF agents resulted in sequestration of TNF in the serum. The levels of serum huTNF were similar for D2E7 or Remicade treated mice. The average huTNF levels decreased from 2 to 0.1 ng/mL as a function of administered dose. Enbrel treated mice, on the other hand, had much higher serum huTNF, reaching levels of 20 ng/mL.
  • mice were sacrificed.
  • Right and left hind limbs were harvested from two mice in each treatment group.
  • Limbs were fixed in 10% neutral buffered formalin and then decalcified.
  • Three consecutive sections from each limb sample were mounted on slides and the coded slides were sent for an independent evaluation by a pathologist.
  • Table 2 Approximate ED 50 (mg/kg) values of D2E7, Remicade or Enbrel for prevention of microscopic signs of arthritis in Tg197 mice D2E7 ED 50 , mg/kg Remicade ED 50 , mg/kg Enbrel ED 50 mg/kg Inflammation 0.1 0.5 0.5 Vascularity 0.1 0.1 1 ⁇ ED 50 ⁇ 5 Cartilage Erosion 0.01 ⁇ ED 50 ⁇ 0.1 0.1 ⁇ ED 50 ⁇ 0.5 0.5 Bone Erosion 0.01 1 ⁇ ED 50 ⁇ 0.1 0.1 ⁇ ED 50 ⁇ 0.5 0.5 ⁇ ED 50 ⁇ 1
  • Results from this experiment are also shown in Figure 5 .
  • Figure 5 three slides from each limb were examined; thus, 6 slides per mouse and 12 slides per treatment group were scored for histopathology.
  • mean ⁇ standard deviation of histopathology scores are indicated in the graph.
  • Most of the lesions were associated with ankle joints and all appeared symmetrical (i.e. similar scores for the left and right limbs for a given mouse).
  • Cartilage degradation resulted mostly from endosteal erosive lesions and was generally less extensive than bone erosion. Inflammation was predominantly mononuclear cells with few PMNs, but no dense PMN loci.
  • the difference among the three anti-TNF agents was most pronounced in microscopic signs of disease activity in the arthritic joints than the external manifestations measured as arthritic scores. Bone erosion in the joints was completely abolished by 0.5 mg/kg dose of D2E7. In order to achieve the same effect a much higher dose of Remicade or Enbrel, 5 mg/kg, was needed. Cartilage erosion in the joints was completely abolished by 0.1 mg/kg dose of D2E7. In order to achieve the same effect a much higher dose of Remicade, 1mg/kg, or Enbrel,5 mg/kg, was needed. Inflammation in the joints was completely abolished by 0.5 mg/kg dose of D2E7.

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10376582B2 (en) 2013-10-16 2019-08-13 Outlook Therapeutics, Inc. Buffer formulations for enhanced antibody stability
US10696735B2 (en) 2015-01-21 2020-06-30 Outlook Therapeutics, Inc. Modulation of charge variants in a monoclonal antibody composition
US11285210B2 (en) 2016-02-03 2022-03-29 Outlook Therapeutics, Inc. Buffer formulations for enhanced antibody stability

Families Citing this family (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6090382A (en) * 1996-02-09 2000-07-18 Basf Aktiengesellschaft Human antibodies that bind human TNFα
BRPI9707379C8 (pt) 1996-02-09 2017-12-12 Abbott Biotech Ltd composições farmacêuticas compreendendo anticorpo humano recombinante geneticamente engenheirado, e anticorpo humano recombinante geneticamente engenheirado.
CA2385745C (en) 2001-06-08 2015-02-17 Abbott Laboratories (Bermuda) Ltd. Methods of administering anti-tnf.alpha. antibodies
US20050271663A1 (en) * 2001-06-28 2005-12-08 Domantis Limited Compositions and methods for treating inflammatory disorders
US20040009172A1 (en) * 2002-04-26 2004-01-15 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
PL218992B1 (pl) * 2002-07-19 2015-02-27 Abbott Biotech Ltd Neutralizujące o wysokim powinowactwie izolowane ludzkie przeciwciało anty-TNFα, zastosowanie tego przeciwciała, kryształ zawierający ludzkie przeciwciało anty-TNFα i preparat zawierający ten kryształ
US20090280065A1 (en) * 2006-04-10 2009-11-12 Willian Mary K Uses and Compositions for Treatment of Psoriasis
US20040033228A1 (en) 2002-08-16 2004-02-19 Hans-Juergen Krause Formulation of human antibodies for treating TNF-alpha associated disorders
MY150740A (en) * 2002-10-24 2014-02-28 Abbvie Biotechnology Ltd Low dose methods for treating disorders in which tnf? activity is detrimental
EP1670787B1 (en) * 2003-09-11 2012-05-30 iTherX Pharma, Inc. Cytokine inhibitors
TW201705980A (zh) * 2004-04-09 2017-02-16 艾伯維生物技術有限責任公司 用於治療ＴＮＦα相關失調症之多重可變劑量療法
GB0414054D0 (en) 2004-06-23 2004-07-28 Owen Mumford Ltd Improvements relating to automatic injection devices
US20060083741A1 (en) * 2004-10-08 2006-04-20 Hoffman Rebecca S Treatment of respiratory syncytial virus (RSV) infection
NZ595225A (en) 2005-05-16 2013-05-31 Abbott Biotech Ltd Use of tnf inhibitor for treatment of erosive polyarthritis
US20070041905A1 (en) * 2005-08-19 2007-02-22 Hoffman Rebecca S Method of treating depression using a TNF-alpha antibody
CN103336129A (zh) * 2005-11-01 2013-10-02 阿布维生物技术有限公司 使用生物标志物诊断强直性脊柱炎的方法和组合物
WO2007058990A2 (en) * 2005-11-14 2007-05-24 Kemia, Inc. Therapy using cytokine inhibitors
US8338397B2 (en) 2006-01-19 2012-12-25 The Regents Of The University Of Michigan Composition and method of treating side effects from antibiotic treatment
USRE46372E1 (en) 2006-01-19 2017-04-25 The Regents Of The Univerity Of Michigan Method for treating hearing loss
US8927528B2 (en) 2006-01-19 2015-01-06 The Regents Of The University Of Michigan Composition for treating hearing loss
US9919008B2 (en) 2006-01-19 2018-03-20 The Regents Of The University Of Michigan Method for treating age-related hearing loss (ARHL)
US7951845B2 (en) 2006-01-19 2011-05-31 The Regents Of The University Of Michigan Composition and method of treating hearing loss
US9889156B2 (en) 2006-01-19 2018-02-13 The Regents Of The University Of Michigan Method for treating noise-induced hearing loss (NIHL)
US10238599B2 (en) 2006-01-19 2019-03-26 The Regents Of The University Of Michigan Composition and method for treating congenital cytomegalovirus induced hearing loss
US9770433B2 (en) 2006-01-19 2017-09-26 The Regents Of The University Of Michigan Composition and method for treating tinnitus
CN102887955A (zh) * 2006-04-05 2013-01-23 艾博特生物技术有限公司 抗体纯化
EP2010214A4 (en) 2006-04-10 2010-06-16 Abbott Biotech Ltd USES AND COMPOSITIONS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
US9605064B2 (en) * 2006-04-10 2017-03-28 Abbvie Biotechnology Ltd Methods and compositions for treatment of skin disorders
WO2008063213A2 (en) 2006-04-10 2008-05-29 Abbott Biotechnology Ltd. Uses and compositions for treatment of psoriatic arthritis
US20080118496A1 (en) * 2006-04-10 2008-05-22 Medich John R Uses and compositions for treatment of juvenile rheumatoid arthritis
EP2012586A4 (en) 2006-04-10 2010-08-18 Abbott Biotech Ltd USES AND COMPOSITIONS FOR THE TREATMENT OF ANKYLOSANTE SPONDYLARTHRITIS
US20090317399A1 (en) * 2006-04-10 2009-12-24 Pollack Paul F Uses and compositions for treatment of CROHN'S disease
US20080131374A1 (en) * 2006-04-19 2008-06-05 Medich John R Uses and compositions for treatment of rheumatoid arthritis
US20100021451A1 (en) * 2006-06-08 2010-01-28 Wong Robert L Uses and compositions for treatment of ankylosing spondylitis
US20080311043A1 (en) * 2006-06-08 2008-12-18 Hoffman Rebecca S Uses and compositions for treatment of psoriatic arthritis
JP5535623B2 (ja) 2006-06-30 2014-07-02 アッヴィ バイオテクノロジー リミテッド 自動注射装置
RU2486296C2 (ru) 2006-10-27 2013-06-27 Эбботт Байотекнолоджи Лтд. КРИСТАЛЛИЧЕСКИЕ АНТИТЕЛА ПРОТИВ hTNFα
WO2008150491A2 (en) * 2007-05-31 2008-12-11 Abbott Laboratories BIOMARKERS PREDICTIVE OF THE RESPONSIVENESS TO TNFα INHIBITORS IN AUTOIMMUNE DISORDERS
KR20100040840A (ko) * 2007-06-06 2010-04-21 도만티스 리미티드 폴리펩티드，항체 가변 도메인 및 길항제
US8999337B2 (en) 2007-06-11 2015-04-07 Abbvie Biotechnology Ltd. Methods for treating juvenile idiopathic arthritis by inhibition of TNFα
EP2173380A4 (en) * 2007-07-13 2011-08-31 Abbott Biotech Ltd METHOD AND COMPOSITIONS FOR PULMONARY ADMINISTRATION OF A TNFa HEMMER
EP2185201A4 (en) 2007-08-08 2011-11-30 Abbott Lab COMPOSITIONS AND METHODS FOR CRYSTALLIZING ANTIBODIES
US8883146B2 (en) 2007-11-30 2014-11-11 Abbvie Inc. Protein formulations and methods of making same
RU2473360C2 (ru) 2007-11-30 2013-01-27 Эббот Лэборетриз Белковые композиции и способы их получения
CA2710333A1 (en) * 2008-01-03 2009-07-09 Abbott Biotechnology Ltd. Predicting long-term efficacy of a compound in the treatment of psoriasis
WO2009090189A1 (en) 2008-01-15 2009-07-23 Abbott Gmbh & Co.Kg Powdered protein compositions and methods of making same
PT2258361E (pt) * 2008-03-27 2014-10-15 Toyama Chemical Co Ltd Utilização de uma combinação de um derivado de benzofenona ou de um seu sal com um inibidor de tnfalfa e composição farmacêutica contendo o referido sal ou derivado e o inibidor
CN102458517B (zh) 2009-04-29 2014-07-23 阿布维生物技术有限公司 自动注射装置
WO2010129469A1 (en) * 2009-05-04 2010-11-11 Abbott Biotechnology Ltd. Stable high protein concentration formulations of human anti-tnf-alpha-antibodies
US8758301B2 (en) 2009-12-15 2014-06-24 Abbvie Biotechnology Ltd Firing button for automatic injection device
HRP20181598T1 (hr) 2010-06-03 2018-11-30 Abbvie Biotechnology Ltd Uporaba i pripravci za liječenje hidradenitis suppurativa (hs)
UY33679A (es) 2010-10-22 2012-03-30 Esbatech Anticuerpos estables y solubles
HRP20161753T1 (hr) 2010-11-11 2017-02-10 Abbvie Biotechnology Ltd Tekuće formulacije protutijela anti-tnf-alfa s visokom koncentracijom
BR112013018905B1 (pt) 2011-01-24 2021-07-13 Abbvie Biotechnology Ltd Dispositivos de injeção automática que têm superfícies de pega sobremoldadas.
US9062106B2 (en) 2011-04-27 2015-06-23 Abbvie Inc. Methods for controlling the galactosylation profile of recombinantly-expressed proteins
WO2012150325A1 (en) * 2011-05-04 2012-11-08 Cellmade Sas Method for finding active pharmaceutical ingredients for the treatment of diseases associated with increased or decreased cytokine pathway activity
EP2520934A1 (en) * 2011-05-04 2012-11-07 CellMade SAS Method for finding active pharmaceutical ingredients for the treatment of deseases associated with increased or decreased cytokine pathway activity
AU2012325232B2 (en) * 2011-10-20 2017-08-31 Esbatech - A Novartis Company Llc Stable multiple antigen-binding antibody
US9067990B2 (en) 2013-03-14 2015-06-30 Abbvie, Inc. Protein purification using displacement chromatography
US9505833B2 (en) 2012-04-20 2016-11-29 Abbvie Inc. Human antibodies that bind human TNF-alpha and methods of preparing the same
US9150645B2 (en) 2012-04-20 2015-10-06 Abbvie, Inc. Cell culture methods to reduce acidic species
US9181572B2 (en) 2012-04-20 2015-11-10 Abbvie, Inc. Methods to modulate lysine variant distribution
US20120323214A1 (en) * 2012-05-16 2012-12-20 Totada R Shantha Alzheimer's disease treatment with multiple therapeutic agents delivered to the olfactory region through a special delivery catheter and iontophoresis
US9249182B2 (en) 2012-05-24 2016-02-02 Abbvie, Inc. Purification of antibodies using hydrophobic interaction chromatography
US9512214B2 (en) 2012-09-02 2016-12-06 Abbvie, Inc. Methods to control protein heterogeneity
KR20150043523A (ko) 2012-09-02 2015-04-22 애브비 인코포레이티드 단백질 불균일성의 제어 방법
US8921526B2 (en) 2013-03-14 2014-12-30 Abbvie, Inc. Mutated anti-TNFα antibodies and methods of their use
US9017687B1 (en) 2013-10-18 2015-04-28 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same using displacement chromatography
US9499614B2 (en) 2013-03-14 2016-11-22 Abbvie Inc. Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosaccharides
AU2014288847A1 (en) * 2013-07-11 2016-01-28 Novartis Ag Use of a VEGF antagonist in treating retinopathy of prematurity
EP3052640A2 (en) 2013-10-04 2016-08-10 AbbVie Inc. Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins
US8946395B1 (en) 2013-10-18 2015-02-03 Abbvie Inc. Purification of proteins using hydrophobic interaction chromatography
US9085618B2 (en) 2013-10-18 2015-07-21 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9181337B2 (en) 2013-10-18 2015-11-10 Abbvie, Inc. Modulated lysine variant species compositions and methods for producing and using the same
US20150139988A1 (en) 2013-11-15 2015-05-21 Abbvie, Inc. Glycoengineered binding protein compositions
US9763992B2 (en) 2014-02-13 2017-09-19 Father Flanagan's Boys' Home Treatment of noise induced hearing loss
US20170183376A1 (en) 2014-06-24 2017-06-29 Insight Biopharmaceuticals Ltd. Methods of purifying antibodies
JP6586454B2 (ja) * 2014-08-14 2019-10-02 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト ヒトｃｄ４０を活性化する抗体とヒトｐｄ−ｌ１に対する抗体との併用療法
ES2913200T3 (es) 2015-03-31 2022-06-01 Sorriso Pharmaceuticals Inc Polipéptidos
CN107438620A (zh) 2015-03-31 2017-12-05 韦斯夸尔德有限公司 多肽
WO2016156466A1 (en) 2015-03-31 2016-10-06 Vhsquared Limited Peptide construct having a protease-cleavable linker
EP3078675A1 (en) 2015-04-10 2016-10-12 Ares Trading S.A. Induction dosing regimen for the treatment of tnf alpha mediated disorders
CN104887687A (zh) * 2015-05-27 2015-09-09 南京医科大学第一附属医院 美莎拉嗪在制备治疗坏疽性脓皮病的药物中的应用
RS62040B1 (sr) 2016-06-02 2021-07-30 Abbvie Inc Agonist receptora glukokortikoida i njegovi imunokonjugati
WO2018060453A1 (en) 2016-09-30 2018-04-05 Vhsquared Limited Compositions
WO2018119142A1 (en) 2016-12-21 2018-06-28 Amgen Inc. Anti-tnf alpha antibody formulations
EP3645009A4 (en) * 2017-06-27 2021-03-31 The Ohio State Innovation Foundation LIPONUCLEOTIDE THERAPY FOR COPD
EP3658192B1 (en) 2017-12-01 2021-04-28 AbbVie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
CN114514243B (zh) 2019-06-21 2025-01-24 索瑞索制药公司 多肽
WO2020254827A1 (en) 2019-06-21 2020-12-24 Vhsquared Limited Polypeptides

Family Cites Families (132)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1208546A (en) 1981-09-08 1986-07-29 Anthony Cerami Lipoprotein lipase suppression by endotoxin-induced mediator (shock assay)
US5672347A (en) 1984-07-05 1997-09-30 Genentech, Inc. Tumor necrosis factor antagonists and their use
IL73883A (en) 1984-12-20 1990-12-23 Yeda Res & Dev Monoclonal antibodies against tnf-alpha,hybridomas producing them and method for the purification of tnf-alpha
US4597966A (en) 1985-01-09 1986-07-01 Ortho Diagnostic Systems, Inc. Histidine stabilized immunoglobulin and method of preparation
EP0212489B1 (en) 1985-08-16 1994-11-30 The Rockefeller University Anabolic activity modulator and uses thereof
US4870163A (en) 1985-08-29 1989-09-26 New York Blood Center, Inc. Preparation of pure human tumor necrosis factor and hybridomas producing monoclonal antibodies to human tumor necrosis factor
EP0230574A3 (en) 1986-01-31 1989-03-22 Yale University Pharmaceutical compositions against infections caused by lav/htlv iii virus and the use thereof
DE3631229A1 (de) 1986-09-13 1988-03-24 Basf Ag Monoklonale antikoerper gegen humanen tumornekrosefaktor (tnf) und deren verwendung
US5237054A (en) 1987-02-20 1993-08-17 Akzo Pharma Stabilized aqueous composition containing antibodies
EP0417191B1 (en) 1988-05-27 1993-03-10 Centocor, Inc. Formulation for antibody reagents
NZ229922A (en) 1988-07-18 1992-04-28 Chiron Corp Monoclonal antibodies specifically binding cachectin (tumor necrosis factor) and compositions
EP0394385A1 (en) 1988-07-27 1990-10-31 BMC Software, Inc. Improved data transmission optimizer
US4897465A (en) 1988-10-12 1990-01-30 Abbott Laboratories Enrichment and concentration of proteins by ultrafiltration
EP0366043B1 (en) 1988-10-24 1994-03-30 Otsuka Pharmaceutical Co., Ltd. Monoclonal antibody
DE68927671T2 (de) 1988-12-19 1997-05-07 American Cyanamid Co Produkte zur Behandlung des Endotoxin -Schocks bei einem Säugetier
CA2064915C (en) 1989-08-07 2001-05-29 Deborah A. Rathjen Tumour necrosis factor binding ligands
US5998378A (en) 1989-08-16 1999-12-07 Chiron Corporation Compositions for the inhibition of TNF hormone formation and uses thereof
GB8921123D0 (en) 1989-09-19 1989-11-08 Millar Ann B Treatment of ards
JPH0791318B2 (ja) 1989-09-21 1995-10-04 三井東圧化学株式会社 蛋白質水溶液、蛋白質水溶液の濃度増大方法および蛋白質製剤
GB8928874D0 (en) 1989-12-21 1990-02-28 Celltech Ltd Humanised antibodies
US5859205A (en) 1989-12-21 1999-01-12 Celltech Limited Humanised antibodies
US5945098A (en) 1990-02-01 1999-08-31 Baxter International Inc. Stable intravenously-administrable immune globulin preparation
DE4037604A1 (de) 1990-04-25 1991-10-31 Bayer Ag Verwendung von anti-tnf-antikoerpern als arzneimittel bei der behandlung von ischaemien und deren folgen
GB9014932D0 (en) 1990-07-05 1990-08-22 Celltech Ltd Recombinant dna product and method
EP0608212A1 (en) 1990-08-27 1994-08-03 Peptide Technology Ltd Method of treating viral infection
GB2279077B (en) 1990-12-21 1995-06-14 Celltech Ltd Therapeutic compositions comprising recombinant antibodies specific for the TNFalpha
US5994510A (en) 1990-12-21 1999-11-30 Celltech Therapeutics Limited Recombinant antibodies specific for TNFα
GB9109645D0 (en) 1991-05-03 1991-06-26 Celltech Ltd Recombinant antibodies
GB9028123D0 (en) 1990-12-28 1991-02-13 Erba Carlo Spa Monoclonal antibodies against human tumor necrosis factor alpha
ATE240740T1 (de) 1991-03-15 2003-06-15 Amgen Inc Pegylation von polypeptiden
EP1857554A1 (en) 1991-03-18 2007-11-21 New York University Monoclonal and chimeric antibodies specific for human tumor necrosis factor
US5698195A (en) * 1991-03-18 1997-12-16 New York University Medical Center Methods of treating rheumatoid arthritis using chimeric anti-TNF antibodies
US7192584B2 (en) * 1991-03-18 2007-03-20 Centocor, Inc. Methods of treating psoriasis with anti-TNF antibodies
US6277969B1 (en) * 1991-03-18 2001-08-21 New York University Anti-TNF antibodies and peptides of human tumor necrosis factor
DK0604418T3 (da) 1991-03-29 1999-06-14 Immunex Corp Isolerede viralproteincytokinantagonister
US6165467A (en) 1991-07-20 2000-12-26 Yoshihide Hagiwara Stabilized human monoclonal antibody preparation
AU665025B2 (en) 1991-09-23 1995-12-14 Cambridge Antibody Technology Limited Production of chimeric antibodies - a combinatorial approach
GB9122820D0 (en) 1991-10-28 1991-12-11 Wellcome Found Stabilised antibodies
AU3244693A (en) 1991-12-17 1993-07-19 Schering Corporation Use of the combination of anti-tumor necrosis factor plus interleukin-6 to treat septic shock
WO1993019751A1 (en) 1992-04-02 1993-10-14 Smithkline Beecham Corporation Compounds useful for treating inflammatory diseases and inhibiting production of tumor necrosis factor
DE69321909T2 (de) 1992-08-28 1999-04-01 Bayer Corp., Pittsburgh, Pa. Verwendung von monoklonalen Anti-TNF-Antikörpern für die Behandlung von bakteriellen Meningitiden
AU670125B2 (en) 1992-09-15 1996-07-04 Immunex Corporation Method of treating tnf-dependent inflammation using tumor necrosis factor antagonists
US6270766B1 (en) 1992-10-08 2001-08-07 The Kennedy Institute Of Rheumatology Anti-TNF antibodies and methotrexate in the treatment of arthritis and crohn's disease
CA2147180A1 (en) 1992-10-15 1994-04-28 Gokhan S. Hotamisligil Treatment of insulin resistance in obesity linked type ii diabetes using antagonists to tnf-.alpha. function
ES2159529T5 (es) 1993-03-05 2011-03-09 Bayer Corporation Anticuerpos monoclonales humanos anti-tnf alfa.
DE4307508A1 (de) 1993-03-10 1994-09-15 Knoll Ag Verwendung von anti-TNF-Antikörpern als Arzneimittel bei der Behandlung von Herzinsuffizienz (Herzmuskelschwäche)
ATE157100T1 (de) 1993-06-03 1997-09-15 Therapeutic Antibodies Inc Antikoerperfragmente in therapie
FR2708467B1 (fr) 1993-07-30 1995-10-20 Pasteur Merieux Serums Vacc Préparations d'immunoglobulines stabilisées et procédé pour leur préparation.
EP0659766A1 (en) 1993-11-23 1995-06-28 Schering-Plough Human monoclonal antibodies against human cytokines and methods of making and using such antibodies
DE4344824C1 (de) 1993-12-28 1995-08-31 Immuno Ag Hochkonzentriertes Immunglobulin-Präparat und Verfahren zu seiner Herstellung
NZ278607A (en) 1994-02-07 1999-05-28 Knoll Ag Use of tnf antagonists for treating disorders involving elevated serum levels of il-6 wherein the serum levels are 500pg/ml or above
EP0748338A4 (en) 1994-03-04 2001-03-28 Merck & Co Inc IN VITRO MATURATION OF ANTIBODIES BY MEANS OF ALANINE 'SCANNING' MUTAGENESIS
ZA955642B (en) 1994-07-07 1997-05-06 Ortho Pharma Corp Lyophilized imaging agent formulation
GB9418092D0 (en) 1994-09-08 1994-10-26 Red Cross Found Cent Lab Blood Organic compounds
US6267958B1 (en) 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
MX9800684A (es) 1995-07-27 1998-04-30 Genentech Inc Formulacion de proteinas liofilizadas isotonicas estables.
US6090382A (en) 1996-02-09 2000-07-18 Basf Aktiengesellschaft Human antibodies that bind human TNFα
BRPI9707379C8 (pt) 1996-02-09 2017-12-12 Abbott Biotech Ltd composições farmacêuticas compreendendo anticorpo humano recombinante geneticamente engenheirado, e anticorpo humano recombinante geneticamente engenheirado.
GB9610992D0 (en) 1996-05-24 1996-07-31 Glaxo Group Ltd Concentrated antibody preparation
GB9705810D0 (en) 1997-03-20 1997-05-07 Common Services Agency Intravenous immune globulin
AU6914998A (en) 1997-04-07 1998-10-30 Cangene Corporation Intravenous immune globulin formulation containing a non-ionic surface active agent with improved pharmacokinetic properties
ES2190087T3 (es) 1997-06-13 2003-07-16 Genentech Inc Formulacion estabilizada de un anticuerpo.
US6171586B1 (en) 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
ES2182202T5 (es) 1997-10-23 2007-12-01 Mitsubishi Pharma Corporation Preparacion de inmunoglobulinas para inyeccion intravenosa apta para ser almacenada a temperatura ambiente.
WO1999037329A1 (en) 1998-01-22 1999-07-29 Astrazeneca Ab Pharmaceutical formulation comprising an antibody and a citrate buffer
US6177077B1 (en) 1999-02-24 2001-01-23 Edward L. Tobinick TNT inhibitors for the treatment of neurological disorders
US6015557A (en) * 1999-02-24 2000-01-18 Tobinick; Edward L. Tumor necrosis factor antagonists for the treatment of neurological disorders
US6419944B2 (en) 1999-02-24 2002-07-16 Edward L. Tobinick Cytokine antagonists for the treatment of localized disorders
US6537549B2 (en) * 1999-02-24 2003-03-25 Edward L. Tobinick Cytokine antagonists for the treatment of localized disorders
US6423321B2 (en) * 1999-02-24 2002-07-23 Edward L. Tobinick Cytokine antagonists for the treatment of sensorineural hearing loss
EP1041072B1 (en) 1999-03-31 2003-07-16 Pfizer Products Inc. Dioxocyclopentyl hydroxamic acids
US20010021380A1 (en) * 1999-04-19 2001-09-13 Pluenneke John D. Soluble tumor necrosis factor receptor treatment of medical disorders
AU4314900A (en) 1999-04-28 2000-11-17 Yamanouchi Pharmaceutical Co., Ltd. Parenteral medicinal composition containing humanized monoclonal antibody fragment and method for stabilizing the same
CA2371095A1 (en) 1999-05-05 2000-11-16 Michela Seveso Enhanced delivery of nucleic acid-based drugs
JP4516711B2 (ja) 1999-12-28 2010-08-04 中外製薬株式会社 安定な抗体組成物及び注射製剤
US6585957B1 (en) 2000-01-25 2003-07-01 Aeropharm Technology Incorporated Medicinal aerosol formulation
DE10022092A1 (de) 2000-05-08 2001-11-15 Aventis Behring Gmbh Stabilisiertes Protein-Präparat und Verfahren zu seiner Herstellung
GB0013810D0 (en) 2000-06-06 2000-07-26 Celltech Chiroscience Ltd Biological products
JP5490972B2 (ja) 2000-08-04 2014-05-14 中外製薬株式会社 タンパク質注射製剤
UA81743C2 (uk) 2000-08-07 2008-02-11 Центокор, Инк. МОНОКЛОНАЛЬНЕ АНТИТІЛО ЛЮДИНИ, ЩО СПЕЦИФІЧНО ЗВ'ЯЗУЄТЬСЯ З ФАКТОРОМ НЕКРОЗУ ПУХЛИН АЛЬФА (ФНПα), ФАРМАЦЕВТИЧНА КОМПОЗИЦІЯ, ЩО ЙОГО МІСТИТЬ, ТА СПОСІБ ЛІКУВАННЯ РЕВМАТОЇДНОГО АРТРИТУ
EP2311492B1 (en) 2000-08-11 2017-10-04 Chugai Seiyaku Kabushiki Kaisha Antibody-containing stabilized preparations
SE0003045D0 (sv) 2000-08-29 2000-08-29 Probi Ab New method
JP4340062B2 (ja) 2000-10-12 2009-10-07 ジェネンテック・インコーポレーテッド 粘度の減少した濃縮タンパク質製剤
WO2002043750A2 (en) 2000-12-01 2002-06-06 Battelle Memorial Institute Method for the stabilizing of biomolecules (e.g. insulin) in liquid formulations
EP2325205A3 (en) 2000-12-28 2011-10-12 Altus Pharmaceuticals Inc. Crystals of whole antibodies and fragments thereof and methods for making and using them
KR20020066778A (ko) 2001-02-13 2002-08-21 한국과학기술연구원 체내 난흡수 물질의 흡수촉진용 조성물과 제형 및 그의제조방법
SE0101256D0 (sv) * 2001-04-06 2001-04-06 A & Science Invest Ab Treatment of low back pain
BR0206160A (pt) 2001-05-25 2004-10-26 Abbott Gmbh & Co Kg Uso de anticorpos anti-tnf como medicamentos no tratamento de distúrbios sépticos de pacientes anêmicos
EP1391209A4 (en) 2001-05-30 2009-12-16 Chugai Pharmaceutical Co Ltd PROTEIN PREPARATION
GB0113179D0 (en) 2001-05-31 2001-07-25 Novartis Ag Organic compounds
CA2385745C (en) * 2001-06-08 2015-02-17 Abbott Laboratories (Bermuda) Ltd. Methods of administering anti-tnf.alpha. antibodies
US7318931B2 (en) 2001-06-21 2008-01-15 Genentech, Inc. Sustained release formulation
US20030113316A1 (en) 2001-07-25 2003-06-19 Kaisheva Elizabet A. Stable lyophilized pharmaceutical formulation of IgG antibodies
TWI334439B (en) * 2001-08-01 2010-12-11 Centocor Inc Anti-tnf antibodies, compositions, methods and uses
JP4342941B2 (ja) 2001-08-29 2009-10-14 中外製薬株式会社 抗体含有安定化製剤
US6818613B2 (en) 2001-11-07 2004-11-16 Ortho-Mcneil Pharmaceutical, Inc. Aqueous sustained-release formulations of proteins
EP1441589B1 (en) 2001-11-08 2012-05-09 Abbott Biotherapeutics Corp. Stable liquid pharmaceutical formulation of igg antibodies
GB0202633D0 (en) 2002-02-05 2002-03-20 Delta Biotechnology Ltd Stabilization of protein preparations
MXPA04007924A (es) 2002-02-14 2005-05-17 Chugai Pharmaceutical Co Ltd Formulaciones en solucion que contienen anticuerpo.
US20030161828A1 (en) 2002-02-19 2003-08-28 Abbott Gmbh & Co. Kg Use of TNF antagonists as drugs for the treatment of patients with an inflammatory reaction and without suffering from total organ failure
PL215168B1 (pl) 2002-02-27 2013-10-31 Immunex Corp Formulacja polipeptydowa
US20040009172A1 (en) 2002-04-26 2004-01-15 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
US20030206898A1 (en) 2002-04-26 2003-11-06 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
WO2004001007A2 (en) 2002-06-21 2003-12-31 Idec Pharmaceuticals Corporation Buffered formulations for concentrating antibodies and methods of use thereof
EP1539212A4 (en) 2002-07-12 2007-05-02 Medarex Inc METHOD AND COMPOSITIONS FOR PREVENTING OXIDATIVE DEGRADATION OF PROTEINS
PL218992B1 (pl) 2002-07-19 2015-02-27 Abbott Biotech Ltd Neutralizujące o wysokim powinowactwie izolowane ludzkie przeciwciało anty-TNFα, zastosowanie tego przeciwciała, kryształ zawierający ludzkie przeciwciało anty-TNFα i preparat zawierający ten kryształ
US20040033228A1 (en) 2002-08-16 2004-02-19 Hans-Juergen Krause Formulation of human antibodies for treating TNF-alpha associated disorders
MY150740A (en) 2002-10-24 2014-02-28 Abbvie Biotechnology Ltd Low dose methods for treating disorders in which tnf? activity is detrimental
US7285269B2 (en) * 2002-12-02 2007-10-23 Amgen Fremont, Inc. Antibodies directed to tumor necrosis factor
TW201705980A (zh) 2004-04-09 2017-02-16 艾伯維生物技術有限責任公司 用於治療ＴＮＦα相關失調症之多重可變劑量療法
US20060083741A1 (en) 2004-10-08 2006-04-20 Hoffman Rebecca S Treatment of respiratory syncytial virus (RSV) infection
NZ595225A (en) 2005-05-16 2013-05-31 Abbott Biotech Ltd Use of tnf inhibitor for treatment of erosive polyarthritis
US20070041905A1 (en) 2005-08-19 2007-02-22 Hoffman Rebecca S Method of treating depression using a TNF-alpha antibody
CN103336129A (zh) 2005-11-01 2013-10-02 阿布维生物技术有限公司 使用生物标志物诊断强直性脊柱炎的方法和组合物
CN102887955A (zh) 2006-04-05 2013-01-23 艾博特生物技术有限公司 抗体纯化
EP2010214A4 (en) 2006-04-10 2010-06-16 Abbott Biotech Ltd USES AND COMPOSITIONS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
WO2008063213A2 (en) 2006-04-10 2008-05-29 Abbott Biotechnology Ltd. Uses and compositions for treatment of psoriatic arthritis
US20090317399A1 (en) 2006-04-10 2009-12-24 Pollack Paul F Uses and compositions for treatment of CROHN'S disease
US20080118496A1 (en) 2006-04-10 2008-05-22 Medich John R Uses and compositions for treatment of juvenile rheumatoid arthritis
EP2012586A4 (en) 2006-04-10 2010-08-18 Abbott Biotech Ltd USES AND COMPOSITIONS FOR THE TREATMENT OF ANKYLOSANTE SPONDYLARTHRITIS
US20080131374A1 (en) 2006-04-19 2008-06-05 Medich John R Uses and compositions for treatment of rheumatoid arthritis
US20080311043A1 (en) 2006-06-08 2008-12-18 Hoffman Rebecca S Uses and compositions for treatment of psoriatic arthritis
US20100021451A1 (en) 2006-06-08 2010-01-28 Wong Robert L Uses and compositions for treatment of ankylosing spondylitis
EP2500413A1 (en) 2006-09-13 2012-09-19 Abbott Laboratories Cell culture improvements
WO2008150491A2 (en) 2007-05-31 2008-12-11 Abbott Laboratories BIOMARKERS PREDICTIVE OF THE RESPONSIVENESS TO TNFα INHIBITORS IN AUTOIMMUNE DISORDERS
EP2152318A4 (en) 2007-06-01 2011-12-07 Abbott Biotech Ltd COMPOSITIONS AND USES FOR THE TREATMENT OF PSORIASIS AND CROHN'S DISEASE
US8999337B2 (en) 2007-06-11 2015-04-07 Abbvie Biotechnology Ltd. Methods for treating juvenile idiopathic arthritis by inhibition of TNFα
EP2173380A4 (en) 2007-07-13 2011-08-31 Abbott Biotech Ltd METHOD AND COMPOSITIONS FOR PULMONARY ADMINISTRATION OF A TNFa HEMMER
RU2473360C2 (ru) 2007-11-30 2013-01-27 Эббот Лэборетриз Белковые композиции и способы их получения
CA2710333A1 (en) 2008-01-03 2009-07-09 Abbott Biotechnology Ltd. Predicting long-term efficacy of a compound in the treatment of psoriasis
WO2009090189A1 (en) 2008-01-15 2009-07-23 Abbott Gmbh & Co.Kg Powdered protein compositions and methods of making same
RU2502800C2 (ru) 2008-01-15 2013-12-27 Эббви Инк. Усовершенствованные векторы экспрессии млекопитающих и их применение

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KAYMAKCALAN ZEHRA ET AL: "Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor.", CLINICAL IMMUNOLOGY (ORLANDO, FLA.) MAY 2009 LNKD- PUBMED:19188093, vol. 131, no. 2, May 2009 (2009-05-01), pages 308 - 316, ISSN: 1521-7035 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10376582B2 (en) 2013-10-16 2019-08-13 Outlook Therapeutics, Inc. Buffer formulations for enhanced antibody stability
US10696735B2 (en) 2015-01-21 2020-06-30 Outlook Therapeutics, Inc. Modulation of charge variants in a monoclonal antibody composition
US11285210B2 (en) 2016-02-03 2022-03-29 Outlook Therapeutics, Inc. Buffer formulations for enhanced antibody stability

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